1. Technical Field
The present invention is related to a method for treating malignancy and autoimmune disorders and for preventing allograft rejection. More particularly, the present invention is directed to treating any human condition or disorder related to the expression of Tac antigen or involving abnormal IL-2- receptor expression, by reacting Tac antigen or IL-2 receptor expressing cells with anti-Tac antibody or a preparation thereof.
2. State of the Art
The normal resting cells of the body, including T cells, do not express IL-2 receptors and thus do not react with a monoclonal antibody anti-Tac that recognizes the human IL-2 receptor. However, in certain conditions, such as in leukemic T cells of patients infected with human T-cell lymphotrophic virus I (HTLV-I-associated Adult T Cell Leukemia), large numbers of IL-2 receptors are constitutively expressed.
The Tac antigen (also referred to herein as “IL-2Rα”) is also expressed in other malignant conditions including the malignant B lymphocytes of Hairy cell leukemia, follicular lymphoma and the Reed-Sternberg cells of Hodgkin's disease. Furthermore, activated T cells expressing the Tac antigen also appear to play a pathogenic role in certain forms of autoimmune disorders, such as type I diabetes and a subset of patients with aplastic anemia. In addition, when cells responding to foreign histocompatibility antigens become activated, they express the Tac antigen and participate in allograft rejection such as in patients receiving vascularized organ allografts and in graft-versus-host disease in patients receiving marrow allografts. Thus, there are a number of clinical circumstances where the expression of Tac-antigen is involved. Clearly, therefore, the elimination of Tac-positive cells using the anti-Tac monoclonal antibodies would be of value in treating or controlling such pathological states.
The use of chemotherapeutic agents has cured some types of cancer. However, many types of cancer either are initially unresponsive or subsequently acquire resistance to chemotherapy. The development of monoclonal antibody technology by Kohler and Milstein (1975 Nature, 256:495) rekindled interest in the use of antibodies targeted to cell surface antigens to treat cancer patients. However, monoclonal antibodies are just beginning to fulfill the promise for immunotherapy inherent in their great specificity for recognizing and selectively binding to abnormal cells. A number of factors underlie the low therapeutic efficacy observed initially. Unmodified murine monoclonal antibodies are immunogenic and elicit a human immune response. Moreover, most of the mouse monoclonal antibodies used were not cytocidal against neoplastic cells in humans. Finally, in most cases the antibodies used were not directed against a vital cell surface structure such as a receptor for a growth factor that is required for both tumor cell proliferation and the prevention of apoptotic cell death induced by factor deprivation.
Adult T-cell leukemia is a malignancy of T lymphocytes with a median survival time of 9 months in the acute and 24 months in the chronic form of the disease. Various combination chemotherapies have not significantly increased the survival of patients with ATL. In light of the disappointing results using conventional combination chemotherapy, IL-2R-directed therapy was developed to exploit the observation that normal resting cells, including the unaffected normal T cells of patients with ATL, do not display IL-2Rα, whereas the leukemic cells express this interleukin receptor subunit.
Hodgkin's disease currently has an annual incidence of 4/100,000 in the United States. Tumors in the lymph nodes of affected patients are composed of nonmalignant lymphocytes far outnumbering the malignant Reed-Sternberg cells, which may express T or B cell markers. 40% of patients will have stage I or II disease, which is curable in >90% of cases with radiation and/or chemotherapy.
Non-Hodgkin's lymphoma is becoming more common in the U.S. The annual incidence, which does not include HIV-related cases, is about 15/100,000, over 30-60% higher than 12 years earlier. It is the most rapidly increasing cause of cancer death in white men and in white women is second only to lung cancer. T-cell varieties include cutaneous and peripheral T-cell lymphomas and lymphoblastic lymphoma. B-cell varieties are more common, and are divided into low, intermediate and high grades.
Peripheral T-cell leukemia/lymphomas including T-cell chronic lymphocytic leukemia (CLL) as well as Ki-1 lymphoma, also known as anaplastic large cell lymphoma, frequently expresses IL-2Rα on the surface of a significant proportion of the malignant cells. The malignant cells of between 21 and 47% of patients with HTLV-I negative peripheral T-cell lymphomas express IL-2Rα on the surface of the malignant cells. Furthermore, the malignant T cells in the skin and lymph nodes of patients with cutaneous T-cell lymphoma (mycosis fungoides and the Sézary syndrome) express the Tac antigen (or IL-2Rα). In addition, virtually all (>95%) of the malignant cells of patients with the hairy cell B-cell leukemia express the Tac antigen, and a proportion of other B-cell lymphomas are also Tac-positive. Finally, true histiocytic leukemias and the Reed-Sternberg cell of Hodgkin's disease also manifest the 55-kD Tac peptide. In addition to the expression of the Tac peptide on the surface of the malignant cells, a released soluble 45-kD form of the Tac peptide (referred to herein as “sIL-2Rα”) appears in the circulation. Elevated concentrations of this soluble form of the IL-2 receptor are present in the circulation of patients with the Tac-expressing malignancies discussed above.
All of these diseases are treatable with the method of the present invention.